Dimethyl fumarate (DMF) inhibits proliferation and induce specific cell death in hepatocellular carcinoma (HCC)

Introduction We could show that dimethyl fumarate (DMF) treatment leads to induction of apoptosis in NF-KB-dependent tumors. In addition, a mouse xerograph model revealed that DMF application led to inhibition of metastasis formation. The inhibition of metastasis formation was NF-κB-independent. Thus, we analyzed NF-KB-independent tumor cell lines (e.g. from colon cancer, pancreatic cancer) regarding migration and invasiveness. DMF reduced these parameters important for metastasis formation in cell lines of these tumors. Here, we analyzed whether DMF application leads to an inhibition of proliferation and cell death induction in hepatocellular carcinoma (HCC) cell lines.

Methods Human HCC cell lines Hep3B, HepG2 and Huh7 were treated with DMF (from 25μM up to 100μM) for up to 72h. The cellular ATP content was measured using a luminescence based assay. To test the effects on proliferation cells were either treated with different DMF concentrations or treated with DMF and 50μM zVAD a caspase inhibitor to prevent induction of apoptosis. HCC cell lines were stained with Cytopainter Cell Proliferation Staining Reagent. The proliferation of the HCC cell lines were monitored up to 96h by flow cytometry. Cell death induction was analyzed by flow cytometry.

Results DMF application resulted in a time and dose-dependent energy (ATP) depletion in all cell lines used. We analyzed whether the decrease in ATP level induces apoptosis or inhibition of proliferation. Interestingly, the DMF treatment resulted in a moderate cell death induction, which was time and dose-dependent. To investigate whether proliferation is effected cells were treated with DMF in combination with zVAD, a caspase inhibitor, to prevent cell death. Accordingly, to the ATP-depletion HCC cell lines showed a strongly diminished proliferation rate.

Conclusion Here, we could show that DMF is capable to inhibit proliferation and induce specific cell death in HCC cell lines. DMF is already clinically approved for treatment of multiples sclerosis and displays only minor side effects. Hence, targeting cellular metabolism by substances like DMF should be regarded as a promising approach to develop novel therapeutic tools to treat solid tumors such as HCC to prevent metastasis formation and tumor growth.

Publication History

Article published online:
04 January 2021